New strategies and therapeutics to overcome the scourge of antibiotic-resistant bacterial infections are urgently needed. Enterococci are among the 3 most common causes of hospital-acquired infections, many of which are caused by enterococcal strains that are resistant to multiple antibiotics, including vancomycin. Systemic infections with antibiotic-resistant enterococci occur subsequent to colonization of the gastrointestinal tract, enabled by antibiotic therapy that leads to massive increases in abundance of drug-resistant enterococci. Thus, strategies to reduce or eliminate GI colonization by antibiotic-resistant enterococci before, during, or after antibiotic therapy represent innovativ approaches to reducing the incidence of antibiotic-resistant enterococcal infection and the spread of antibiotic-resistant isolates. We will use a new mouse model of GI colonization by enterococci with features that mimic the antibiotic-induced enterococcal expansion observed in humans to explore strategies to reduce enterococcal GI colonization. In particular, the research proposed here seeks to use lytic enterococcal bacteriophage to achieve reductions in enterococcal abundance in the mammalian GI tract before or during antibiotic therapy as a means of preventing infection by antibiotic-resistant enterococci.